The present invention relates to novel pyrazine-2-carboxamide derivatives, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful in treating diseases associated with the modulation of CB2 receptors.
Two different subtypes of cannabinoid receptors (CB1 and CB2) have been isolated and both belong to G protein coupled receptor superfamily. Alternative spliced forms of CB1, CB1A and CB1B have also been described, but are expressed only at low levels in the tissues tested. (D. Shire, C. Carrillon, M. Kaghad, B. Calandra, M. Rinaldi-Carmona, G. Le Fur, D. Caput, P. Ferrara, J. Biol. Chem. 270 (8), 1995, 3726-31; E. Ryberg, H. K. Vu, N. Larsson, T. Groblewski, S. Hjorth, T. Elebring, S. Sjögren, P. J. Greasley, FEBS Lett. 579, 2005, 259-264). The CB1 receptor is mainly located in the brain and to a lesser extent in several peripheral organs, whereas the CB2 receptor is predominately distributed in the periphery primarily localized in spleen and cells of the immune system (S. Munro, K. L. Thomas, M. Abu-Shaar, Nature 365, 1993, 61-61). Therefore in order to avoid side effects a CB2-selective compound is desirable.
Δ9-tetrahydrocannabinol (Δ9-THC) is the principal psychoactive compound in the Indian hemp (Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc., 86 (1964) 1646), cannabis sativa (marijuana), and has medicinal uses (R. Mechoulam (Ed.) in “Cannabinoids as therapeutic Agents”, 1986, pp. 1-20, CRC Press). Δ9-THC is a non-selective CB1/2 receptor agonist and is available in the USA as dronabinol (Marinol®) for the alleviation of cancer chemotherapy-induced emesis (CIE) and the reversal of body weight loss experienced by AIDS patients through appetite stimulation. In the UK Nabolinone (LY-109514, Cesamet®), a synthetic analogue of Δ9-THC, is used for CIE (R. G. Pertwee, Pharmaceut. Sci. 3 (11), 1997, 539-545, E. M. Williamson, F. J. Evans, Drugs 60 (6), 2000, 1303-1314).
Following the cloning of CB1- (1990) and CB2-receptors (1993) two endocannabinoids (2-arachidonoylethanolamide (=anandamide) and 2-arachidonoylglycerol (2-AG)) were identified and further characterized. Subsequently, notable studies appeared showing anti-inflammatory properties of cannabinoids like Δ9-THC or metabolites of THC.
CB2 receptor selective agonists/ligands are considered to be useful for the treatment of inflammatory disorders such as rheumatoid arthritis, asthma and chronic obstructive pulmonary disease while being devoid of psychotropic effects associated with CB1 receptor agonism (J. Hynes, K. Leftheris, Bioorganic & Medicinal Chemistry Letters 12, 2002, 2399-2402). It is therefore an object of this invention to provide selective, directly acting CB2 receptor agonists/ligands. Such agonists/ligands are useful in medical therapy, particularly in the treatment and/or prevention of diseases which are associated with the modulation of CB2 receptors.